-----------------------------------------------------------------------Copyright © 1998 by The Johns Hopkins University Press. All rights
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Kennedy Institute of Ethics Journal 8.2 (1998) 131-144
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The Question Not Asked: The Challenge of Pleiotropic Genetic Tests
Robert Wachbroit
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Abstract. Nearly all of the literature on the ethical, legal, or social issues
surrounding genetic tests has proceeded on the assumption that any particular test
for a gene mutation yields information about only one disease condition. Even
though the phenomenon of pleiotropy, where a single gene has multiple,
apparently unrelated phenotypic effects, is widely recognized in genetics, it has
not had much significance for genetic testing until recently. In this article, I
examine a moral dilemma created by one sort of pleiotropic testing, APOE
genotyping, which can yield information about the risk of two different
conditions--coronary heart disease and Alzheimer's disease. A physician
administering APOE testing for the beneficial purpose of assessing the risk of
heart disease may discover medically useless and socially harmful information
about the patient's risk of Alzheimer's disease. I explore how much providers
should disclose to patients about pleiotropic test results and whether patients are
obligated to know as much about their genetic condition as possible.
Discussion regarding genetic testing have gone through two stages. Inthe first, the
focus was primarily on single- gene disorders--those in which a particular gene
mutation is causally necessary and sufficient for a disease to occur. These
discussions centered on the ability of genetic tests to predict the onset of a disease
or to confirm its diagnosis and on the associated ethical issues, such as who should
have access to this information, what restrictions should be placed on its use, and,
in the case of diseases where therapies were not yet available, whether the genetic
tests should be performed at all. While these concerns were important, they did not
seem applicable to many situations, since single-gene disorders such as
Huntington's disease are relatively rare. [End Page 131]
In the second stage, attention has centered on more common diseases to which
genes have a more complex relation--those for which a genetic mutation may be
neither causally necessary nor sufficient for the occurrence of the disease.
Discussions now focused on diseases such as cystic fibrosis, various types of
cancer, and heart diseases, where the presence of particular environmental
conditions or family histories is an essential part of the causal nexus that links a
specific genetic mutation and a disease. (Indeed, in some cases the genetic
mutation may not even be a partial cause but rather a risk factor--e.g., the genetic
mutation may be associated with a disease via a causal factor common to them
both.) These discussions have responded to the complexity of the connection
between genes and diseases by adding considerations of risk communication and
risk perception to the earlier concerns about privacy, discrimination, and other
issues.
For the most part, second-stage discussions have addressed only one type of
complex causal relation, called "heterogeneity," where multiple gene mutations are
involved in a single disease. The converse type of complexity, called "pleiotropy,"
where a single-gene mutation is involved in multiple, apparently unrelated
diseases, has received hardly any attention at all. This relative neglect, insofar as it
is intentional, might indicate a belief that pleiotropy raises no special ethical
issues. Perhaps it has been assumed that if a single genetic test indicates a risk of
contracting two (apparently unrelated) diseases, the ethical issues it raises are
identical to those raised if two distinct tests, one for disease A and the other for
disease B, had been performed. On this view, pleiotropic genetic tests may be
more efficient ("two conditions for the price of one"), but they do not raise ethical
questions different from those created by two separate tests.
This conclusion would be justified if the response to concerns raised by disease A
were always compatible with the response to concerns raised by disease B. If,
however, there is a conflict--e.g., the recommendations regarding testing for
disease A conflict with the recommendations regarding testing for disease B--then
the pleiotropic genetic test would appear to present a special ethical issue. The
latter possibility is not merely theoretical. The test for the allele of the APOE gene
is a case in point.
Apoe Genotyping
Coronary heart disease (CAD) and Alzheimer's disease (AD) are two apparently
unrelated diseases. Nevertheless, testing for the *4 allele of the apolipoprotein E
(APOE) gene can yield information about both conditions.[End Page 132] A
positive test result indicates a high risk of hyperlipidemia and, consequently, a
high risk of atherosclerosis and myocardial infarction (Wilson et al. 1994). At the
same time, for reasons we do not fully understand, a positive test result is strongly
associated with a high risk of contracting AD (Strittmatter et al. 1993). Because of
the profound differences in our understanding of these two diseases and in their
social meanings, this pleiotropic test appears to generate a moral dilemma.
On the one hand, since CAD is in many cases treatable, there are clear medical
benefits to administering an APOE test to identify those at risk. Problems of
discrimination in employment or insurance as a result of being tested might arise
in particular situations, but they rarely will outweigh the benefits of treatment.
Thus the APOE test is part of the cardiologist's standard repertoire. On the other
hand, since AD is, as yet, untreatable, the medical benefit of a test that might
identify those at risk is unclear. Furthermore, there are considerable uncertainties
in the interpretation of an APOE test for AD. Because of these uncertainties as
well as the lack of a treatment, many researchers have concluded that APOE
genotyping should not be used either as the sole diagnostic tool or as a predictive
tool for AD (Mayeux et al. 1998). Given the various harms resulting from the
belief that an individual is at risk for AD, including stigmatization, discrimination,
and the psychological burden associated with the prospect of having AD, several
commentators and organizations, including the National Institute on Aging, the
Alzheimer's Association (NIA/AA 1996), the American College of Medical
Genetics, and the American Society of Human Genetics Working Group on ApoE
and Alzheimer Disease (ACMG/ASHG 1995), have recommended against using
the APOE test at this time to assess AD risk.
Here we have one of the starkest conflicts generated by a pleiotropic genetic test.
In the context of CAD, APOE genotyping is clinically useful and accordingly
recommended when appropriate. In the context of AD, however, APOE
genotyping is deemed harmful and is not recommended. Thus, we can have a
situation in which a physician administers APOE testing for the beneficial purpose
of CAD risk assessment but, in the process, discovers socially harmful or
medically useless information about the patient's risk of AD. In what follows, I
will explore how such apparent conflicts might be resolved.
I focus on the APOE test in order to make the discussion of pleiotropic genetic
testing concrete. The APOE test exemplifies the type of moral dilemma that seems
to emerge from pleiotropic genetic testing. It is important [End Page 133] to
realize, however, that the particular conflict between the benefits and the harms of
APOE testing depends upon the current state of medical science. The availability
of a treatment for AD would most likely change the nature of the case but the
general questions would remain: When a genetic test may reveal information
about two (or more) unrelated conditions, how much should providers disclose to
patients? Further, should patients feel obligated to know as much as possible about
their genetic condition? As I explore the first question, I shall assume that if the *4
allele of the APOE gene were associated only with AD, testing would not be
performed except possibly to support a diagnosis of AD. Later, in an effort to
answer the second question, I will drop that assumption (cf. Wachbroit 1996).
Is There an Obligation to Disclose?
Thus far I have presented the conflict arising from pleiotropic genetic tests only as
whether to administer such a test--e.g., do the medical benefits of a CAD risk
assessment outweigh the social and psychological costs of an apparent AD risk
assessment? However, none of the organizations that have recommended against
using APOE genotyping for AD risk have made a recommendation against the
clinical use of APOE altogether. No one has urged that cardiologists cease using
APOE genotyping for the purpose of CAD risk assessment. Indeed, it would be
difficult for health professionals to justify forgoing the clear medical benefits of
performing the test simply because of the possible social and psychological costs
of learning unintended results. Consequently, the issue is not whether the health
professional should ever consider administering the test but rather, when a
particular use of the test is indicated and appropriate, what the patient should be
told. There are three possible responses: compartmentalization, partial disclosure,
and consolidation.
Compartmentalization consists of treating the pleiotropic test as if it were two
separate tests. With this approach, when the cardiologist uses APOE testing for
CAD risk, he or she ignores any information obtained that might indicate a
condition other than the one being tested for. By classifying genetic tests in terms
of the conditions that they test for, we can easily fail to see the conflicts arising
from pleiotropy. For example, in the ACMG's recommendation not to offer APOE
testing for susceptibility to AD, no mention is made of the use of this test in
identifying CAD risk. It focuses exclusively on one disease. [End Page 134]
Part of the rationale for compartmentalization is that it is of a piece with medical
specialization. A neurologist, for example, is not likely to order tests regarding a
patient's cardiac condition. One could argue that the results of pleiotropic tests are
intended as tools for particular specialties, so that, when medical information is
revealed that is outside the clinician's specialty, she can regard it as none of her
concern. Nevertheless, this appeal to medical specialization cannot take us very
far. No one would argue that if a neurologist prescribes medication, he or she can
ignore any cardiac effects the drug might have. Similarly, genetic tests can have
"side effects"--consequences in terms of yielding information other than that
explicitly being sought. Acting as if they do not is indefensible because the
responsibilities of physicians towards their patients are not so neatly
compartmentalized.
The difficulties raised by compartmentalization might suggest the need for a more
flexible approach--partial disclosure. This approach consists of not informing the
patient of the alternative, and presumably unintended, use of the pleiotropic test
before the test is administered, but informing the patient later if the test indicates
that the patient is at risk for the other disease. Thus the cardiologist practicing
partial disclosure uses the APOE test without telling the patient that it may reveal
the risk of AD as well as CAD. The patient is informed of this only if the test
reveals an AD risk. This approach can be justified by drawing an analogy to what
patients must be told about medication. Only the adverse side effects of a drug
need to be disclosed, not all side effects. Similarly, with the partial disclosure
approach, only the adverse side effects of a genetic test, should they occur, need to
be disclosed.
Part of the appeal of this approach is that it does not burden health professionals
with matters outside their area of specialization. The cardiologist administering an
APOE test can be a cardiologist, confining herself to investigating cardiac issues.
She needs to alert the patient to neurological issues only if the test indicates that
the patient is at risk for AD. Furthermore, partial disclosure avoids having the
benefits of the test from the standpoint of CAD overshadowed by the harms from
the standpoint of AD. If patients were told that the test could reveal whether they
were at risk for AD, some of them might choose not to be tested. They would
rather not know anything about their risk of AD, even if that meant forgoing the
benefits of learning about their risks of CAD.
Nevertheless, this partial disclosure approach faces at least two immediate
problems. First, the analogy to disclosing a drug's adverse side effects [End Page
135] is flawed in several respects. In some situations, especially where close
relatives are suffering from a genetic disease, even a negative test result--showing
no increased risk of the disease--can be unwelcome. Some patients might
experience "survivor guilt" as they contemplate the prospects of their less
fortunate siblings or other relatives. The fear of survivor guilt is sometimes an
important reason why patients do not want to be tested for a genetic condition.
Thus, unlike the physician in the medication analogy, a physician performing a
genetic test would have to treat every test result as having a potential adverse side
effect. One could also argue that since learning that one is at risk of AD is itself a
harm--albeit a social harm or psychological burden--the medication analogy
completely fails. The reasoning that leads to informing patients about the risks of
adverse side effects from medication before they take the medication should also
lead to informing patients about the adverse effects of learning that one is at risk
for AD before they take the genetic test.
A different way of justifying partial disclosure might be based on problems with
the quality of the information about AD risk obtained from the test. One does not
have to inform a patient of all possible risks or consequences arising from a
particular medical procedure, but only those that are well established. As noted
earlier, there is some uncertainty about the predictive value of APOE genotyping
for AD. The cardiologist might conclude that there is no clear and well-established
risk of developing AD revealed by the test, and therefore no need to raise that
possibility with the patient. If we consider more controversial associations for
which genetic testing could be carried out, such as the alleged connection between
certain genes and violent behavior, one can argue that the physician is justified in
not informing the patient about such possible associations because they are too
hypothetical. Physicians ought to avoid misleading their patients, the argument
could go, and uncertain information can sometimes be more misleading than no
information.
There are two responses to this argument. First, there is no basis for the general
claim that patients will be misled. Uncertain or ambiguous information is not
necessarily misleading--presumably, the physician is not misled by it.
Consequently, whether a particular patient would be unavoidably misled by it is an
empirical matter. Second, physicians must bear in mind that they are not the only
sources of information their patients have. Genetics is a favorite topic for many
reporters, but not all the reporting in newspapers or television on advances in
genetics is accurate or even responsible. Physicians have no control over what fills
their silence, [End Page 136] and so cannot claim that being silent will protect
patients from being misled. If the concern is about not misleading the patient, then
surely the patient is less likely to be misled by a careful disclosure from a
professional than by the haphazard gleanings of a report on the evening news.
A third way of defending the partial disclosure approach is to invoke a simplified
version of the doctrine of double effect. As this principle is understood in many
medical discussions, an action with bad consequences can be morally justified as
long as these consequences were unintended and the action was performed with a
good intention. This doctrine is usually discussed in the context of treating those at
the end of life. Although deliberately causing the death of a terminally ill patient is
prohibited, administering high doses of pain medication to relieve the patient's
suffering is permissible, according to the doctrine, even though this treatment may
hasten the person's death (Quill, Dresser, and Brock 1997). Accordingly, one
might argue that if assessing CAD risk is the intended use of APOE testing, the
unintended but foreseen negative consequences of learning of an AD risk do not
determine the ethical character of the test.
The doctrine of double effect is extremely controversial, so appealing to it may not
be a good strategy. But even if we put the objections to that doctrine aside, its
applicability to the issue of pleiotropic tests is too strained to be useful. The
doctrine is invoked in discussions regarding the permissibility of certain actions.
However, the issue with pleiotropic testing is not so much the permissibility of
testing as what should be acknowledged and disclosed about what the testing may
reveal. Even staunch supporters of the doctrine of double effect do not claim that
the unintended bad consequences of an action need not be acknowledged or
disclosed.
But the most serious problem with the partial disclosure approach is that it ignores
(or violates) the need for pre-test informed consent. If we hold that patients have
the right to refuse genetic tests because of what might be discovered, then consent
is required in order to administer the tests. In the case of pleiotropic tests, if
patients are not informed of the unintended as well as the intended uses of the
tests, their consent is clearly not informed. Their right to refuse to be tested has not
been respected.
These difficulties with partial disclosure lend support to the practice of
consolidation. This approach consists of informing the patient that the pleiotropic
genetic test is, in fact, pleiotropic. The patient is told about the unsought
information that the pleiotropic test might reveal and must consent to the
unintended as well as the intended medical uses of the test [End Page 137] before
it can be administered (cf. Post et al. 1997). The main argument for consolidation
lies in its apparent emphatic acknowledgment that the patient's autonomy must be
respected and that such respect requires not withholding information even if it
pertains to an unintended use of the genetic test. One unfortunate consequence of
this approach is that people who would benefit from a particular test--as in CAD
risk assessment--might refuse because of worries about the unintended
information obtained--as in AD risk assessment. But this consequence is of a piece
with that resulting from a patient's refusal of treatment and thus is acceptable.
A different problem with consolidation concerns the clinical requirements for each
medical use of the test. When two separate tests are given, the clinical
requirements for each can be quite different. However, as one of the few writers
who has discussed pleiotropic genetic tests has argued, the clinical requirements
regarding any use of a pleiotropic test would be set by its most problematic use
(Juengst 1998). The reason for this is that the potential harms resulting from a test
need not depend upon which use of the pleiotropic test is intended. Insofar as a
concern about these harms shapes the clinical requirements for administering a
test, they would seem to govern the test, regardless of its intended use. The most
restrictive requirements--which would be those associated with the most
problematic use of the test--would therefore dominate. The component of this
requirement or "standard of practice" at issue here is genetic counseling.
It has become common to assert the need for some counseling whenever genetic
testing is performed or even considered, with the nature and amount of counseling
depending on the condition at issue. From the standpoint of the consolidation
approach, genetic counseling for a pleiotropic test would have to cover its
unintended uses as well as its intended ones. Educating the patient about the
various kinds of information the pleiotropic test could yield would not seem to be
especially burdensome for the physician, who should know about the different
clinical uses of any pleiotropic test he or she would propose to administer. But if
the clinical requirements or the standard of practice for administering a test call for
an extension of the clinician's responsibilities to include a great deal more, such as
making available "psychiatric care, support group, and pastoral care" (cf. NIA/AA
1996, p. 1093), these duties might go beyond the resources, time, and abilities of
physicians within particular specialties. A cardiologist might not have the
appropriate professional expertise and resources that, according to the standard of
practice, are essential for [End Page 138] adequate AD testing. Thus, Juengst
(1998) reluctantly concludes that because the cardiologist generally cannot meet
this component of the standard of practice, she will have to abandon APOE
genotyping as a clinical tool.
This argument is not about principles, but about contingent matters of current
institutional structures and resource allocation. Hence, one could respond by
arguing for appropriate changes in resources, and the like, to accommodate this
need for genetic counseling for pleiotropic tests. For example, one could maintain
that cardiologists administering the APOE test should be equipped with the
resources to provide their patients with genetic counseling regarding AD risk. I
would like to explore a different response to this argument. Many of the problems
raised by pleiotropic tests involve the harms that can arise from possessing genetic
information about oneself. I want to examine more carefully the concern with
those harms and the belief that there is a routine need for genetic counseling in
connection with genetic testing.
I noted earlier that receiving genetic information is sometimes portrayed as a
situation fraught with potential social and psychological harms and that genetic
counseling is therefore considered necessary to help the patient cope. This is a
distortion of the purpose of genetic counseling. The need for genetic counseling is
not based on the special severity of the harms associated with genetic information;
it is based on a reaction to the history of eugenics. In an effort to emphatically
distance themselves from the uncomfortably recent history of eugenics, health
professionals take special measures--typically by providing genetic counseling
services--to help people make decisions about the use of genetic information
without coercion or other threats to their autonomy (Wachbroit and Wasserman
1995). The expansion of these services to include efforts to help the patient
anticipate and cope with the results of genetic testing, while not itself
objectionable, has led to an assumption that the act of obtaining genetic
information subjects the patient to otherwise avoidable social harms and
psychological burdens. This act takes on the aspect of engaging in risky behavior,
justified only if there are sufficient medical benefits.
If we take the historical rationale seriously, the strongest case for genetic
counseling is in the area of reproduction. This was where most eugenics policies
were targeted and where we therefore need to be most sensitive to the possibilities
of coercion or other threats to autonomy. The expansion of genetic counseling to
other areas of medicine, however, where [End Page 139] there is no reason to
expect a special threat to autonomy, encourages a "genetic exceptionalism," as if
the mere fact that genetic methodologies were used requires providing the patient
with special support and care. This genetic exceptionalism is dubious at best.
Compare the case of a patient who learns he is at risk of heart disease from an
echocardiogram with the case of a patient who learns that she is at risk of heart
disease from a genetic test. It seems strange to claim that the latter patient, as a
matter of routine procedure or of clinical requirements should receive counseling,
but not the former. There need be no difference between these two cases regarding
possible social or psychological harms. Of course, in certain situations and for
certain individuals, counseling and other support services are indicated and
appropriate. But to insist that counseling should be routinely provided whenever
the medical test is genetic leads to a mystique surrounding the idea of genes that
encourages misunderstandings about what genes are and distorts their significance.
(It should be noted that one could reject genetic exceptionalism but take the
argument in a different direction: All medical tests, genetic and nongenetic, should
routinely be accompanied by pre- and post-test counseling. This would involve
either a drastic strain on resources or a radical reallocation. The merits of either
proposal deserve more discussion than I can give here.)
If a patient, because of his psychological or emotional state, should be offered
special counseling services before undergoing AD testing, then those services
should also be in place if he undergoes CAD testing using APOE genotyping. But
neither the genetic character of this test nor the information it may reveal requires
that such services be routinely provided. Absent special concerns about the
patient's psychological state, there is no need for the cardiologist to provide special
clinical services such as pastoral or psychiatric care. The cardiologist, therefore,
can use APOE testing as a clinical tool, informing the patient of the other clinical
uses of the test. Indeed, even if the test were used for AD risk assessment, these
extraordinary counseling services would not be routinely required procedures. The
situation is different, however, if the use of the pleiotropic test is related to
reproduction. Then Juengst's argument that any use is subject to the standards
governing the most problematic use prevails and counseling services would be
required. But in such cases, this will not be much of an added burden, since
reproductive testing programs will (or should) already have these services in place.
[End Page 140]
Is There an Obligation to Know?
Finally, it is time to challenge one of the assumptions underlying the
recommendation that APOE genotyping for AD risk would be inappropriate.
Recall that the basis for the recommendation is concern that uncertain or
ambiguous test results could give rise to considerable social and psychological
harms without offsetting medical benefit. This assessment, however, rests on
construing harms too broadly and benefits too narrowly. In order to make the
discussion of this point clearer, let us suppose that the uncertainty or ambiguity of
the information were no longer a problem. Would the recommendation against
direct AD testing be justified?
A principal harm often cited in assessing the costs of AD testing is the risk of
discrimination and stigmatization. This harm is real and, perhaps, substantial.
Nevertheless, we should keep in mind where the fault lies. If a patient becomes
uninsurable when a genetic condition is discovered, the proper target for criticism
is the insurance industry, not the discovery. If someone suffers unfair employment
discrimination because of a genetic test result, the fault lies with the practices of
the workplace, not with the information revealed by the test. No thoughtful person
should be misled on this point. Many discussions--not only in the ACMG
recommendations, but also in arguments that have sometimes been made on behalf
of a right not to know--are based on the assumption that the sensible response to
potential harms arising from genetic information is to avoid obtaining the
information, as if by not knowing or not obtaining the information the harm has
been averted.
The inadequacy of this reply can be made clear by imagining how this dilemma
would look in a different context. Consider the harms associated with the
prejudice and discrimination suffered by African-Americans. Although the victims
of this discrimination are usually identified by skin color and other features, the
structure of the prejudice often follows a "one drop of blood" rule: the offspring of
African-Americans may be subject to the same discrimination even if they do not
happen to have the skin color or features typically associated with AfricanAmericans. Imagine the case of someone whose parents are unknown and whose
skin color and features are "White." It might be thought risky for such a person to
trace her roots. Information about her parents might result in social harms and
psychological burdens if it indicates that she has an African ancestry and she then
suffers racial discrimination as a result. Nonetheless, most [End Page 141] people
would agree that advising her not to seek information about her ancestry, or to do
so only if counseling were available, would be offensive even if the advice were
well-meant. It would presume that her legitimate interests in knowing about
herself should defer to the costs arising from unjust social practices. Of course, I
am not suggesting that one's race is like a disease; my point is that many of the
social and psychological risks associated with the discovery of racial heritage and
of genetic conditions are comparable and should receive no greater weight in one
context than in the other.
At the same time, the benefits of AD testing, assuming a reliable test, have been
obscured by an overly narrow focus on medical outcomes. I certainly do not wish
to minimize the harms of genetic discrimination and other burdens. Nevertheless,
the prevailing picture is too one-sided. It leaves out the value we can sometimes
discern in knowing our genetic condition even in the absence of medical benefits.
(In the racial example above, citing possible medical benefits in knowing one's
ancestry hardly captures the importance someone might attach to knowing.) It also
fails to acknowledge the obligation we sometimes have to know our genetic
condition.
The idea that we can sometimes have an obligation to know our genetic condition
has not received nearly as much attention as have the harms arising from such
knowledge, but it is at least as significant. Most of us are enmeshed in a network
of personal obligations and commitments to family members, dependents, and
other loved ones. In many cases, if we have information about our medical
condition, we can more effectively discharge these obligations, or at least avoid
measures that, under the circumstances, may be futile. Consider the case of a 40year-old parent of minor children who refuses to know whether he is at high risk
of contracting AD within the next ten years. His refusal might be irresponsible; it
might amount to a failure to engage fully in the planning that is indicative of a
parent's commitment to his children. The strength of the moral obligation to know
one's genetic condition will depend upon the particulars of the situation. In all
likelihood, however, a person's responsibility to know will not depend upon the
strength of his or her desire to know or not to know.
The idea of having an obligation to know can seem jarring at first. We are drawn
to a picture of an individual, faced with the prospect of knowing, weighing how
that knowledge would affect the quality of his or her [End Page 142] life. The
thought that someone ought to know seems to go against our cultural assumptions,
as if such an obligation were an unwelcome interference in the private relationship
a person has with his or her life. The problem with this picture of solitary
individuals contemplating whether to know about their future is that it fits so few
of us.
The assessment of a genetic test is therefore much more complicated than any
weighing of medical benefits against social or psychological harms. Indeed, as the
above example suggests, there can be an obligation to know that trumps the
considerations of these harms and benefits. This trumping would cut across all
uses of a pleiotropic test.
Robert Wachbroit, Ph.D., is a Research Scholar at the Institute for Philosophy and
Public Policy at the University of Maryland.
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